EPIK-O: A Phase III, Multi-center, Randomized (1:1), Open-label, Active-controlled, Study to Assess the Efficacy and Safety of Alpelisib (BYL719) in Combination With Olaparib as Compared to Single Agent Cytotoxic Chemotherapy, in Participants With no Germline BRCA Mutation Detected, Platinum-resistant or Refractory, High-grade Serous Ovarian Cancer
试验速览
- 阶段
- 3 期
- 状态
- 终止
- 入组人数
- 358
- 试验地点
- 108
- 主要终点
- Progression Free Survival (PFS) based on Blinded Independent Review Committee (BIRC) assessment using RECIST 1.1 criteria
研究概览
简要总结
The objective of this study was to assess the efficacy and safety of the combination of alpelisib and olaparib compared with single agent cytotoxic chemotherapy in patients with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected.
详细描述
This study included adult women with platinum resistant or refractory high-grade serous ovarian cancer, with no germline BRCA mutation detected. Participants were randomized in a 1:1 ratio to either alpelisib plus olaparib or single agent cytotoxic chemotherapy (paclitaxel or PLD) in this open-label, active controlled study.
Participants continued to receive study treatment until disease progression, unacceptable toxicity that precludes further treatment, or until discontinuation of study treatment due to any other reason. After treatment discontinuation, all participants entered in the post-treatment follow-up period, which consisted of a safety follow-up visit and a 9-week post-progression visit. Once they completed the post-treatment follow-up, participants then entered the survival follow-up period.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participant has histologically confirmed diagnosis of high-grade serous or high-grade endometrioid ovarian cancer, fallopian tube cancer, or primary peritoneal cancer
- •Measurable disease, i.e., at least one measurable lesion per RECIST 1.1 criteria (a lesion at a previously irradiated site may only be counted as a target lesion if there is clear sign of progression since the irradiation)
- •If no measurable disease is present, the disease should be assessable by Gynecologic Cancer Intergroup criteria (GCIC) for CA-125
- •Participant has no germline BRCA1/2 mutation as determined by an FDA-approved assay
- •Participant has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Participant has platinum-resistant (progression within one to six months after completing platinum-based therapy) or platinum refractory disease (progression during treatment or within 4 weeks after the last dose), where platinum-based therapy is not an option, according to the GCIG 5th Ovarian Cancer Consensus Conference definitions (Wilson et al 2016). The platinum-based chemotherapy regimen does not necessarily need to be the last regimen the participant received prior to study entry
- •Participant must have received at least one but no more than three prior systemic treatment regimens and for whom single-agent chemotherapy is appropriate as the next line of treatment
- •Participant has received prior bevacizumab or is not eligible to receive bevacizumab due to medical reasons.
排除标准
- •Participant has received prior treatment with any PI3K, mTOR or AKT inhibitor
- •Participant is concurrently using other anti-cancer therapy
- •Participant is in a state of small or large bowel obstruction or has other impairment of gastrointestinal (GI) function or GI disease
- •Participant has had surgery within 14 days prior to starting study drug or has not recovered from major adverse effects
- •Participant has not recovered from all toxicities related to prior anticancer therapies to baseline or NCI CTCAE Version 4.03 Grade ≤
- •Exception to this criterion: participants with any grade of alopecia are allowed to enter the study
- •Participant has an established diagnosis of diabetes mellitus type I or uncontrolled type II based on fasting plasma glucose and HbA1c
- •Participants with liver impairment and Child Pugh score B or C
- •Participant has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to randomization, and who has not recovered to baseline, grade 1 or better from related adverse effects of such therapy (with the exception of alopecia)
- •Participant has a known hypersensitivity to any of the study drugs or excipients
- •Participant has a history of myelodysplastic syndrome or acute myeloid leukemia, or presents clinical and/ or laboratory features suggestive thereof.
- •Other inclusion/exclusion criteria may apply
研究组 & 干预措施
Alpelisib+olaparib
Alpelisib (200 mg once daily after food) and Olaparib (200 mg twice daily) were both administered orally on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle.
干预措施: Alpelisib (Drug)
Alpelisib+olaparib
Alpelisib (200 mg once daily after food) and Olaparib (200 mg twice daily) were both administered orally on a continuous dosing schedule starting on Cycle 1 Day 1 in a 28-day cycle.
干预措施: Olaparib (Drug)
结局指标
主要结局
Progression Free Survival (PFS) based on Blinded Independent Review Committee (BIRC) assessment using RECIST 1.1 criteria
时间窗: From randomization until the date of the first documented progression or death due to any cause, whichever comes first, assessed up to approximately 23 months
Progression-free survival (PFS) was defined as the time from randomization until the first documented disease progression or death from any cause, based on BIRC assessment. Participants without an event were censored at the date of their last adequate tumor assessment. Clinical deterioration without objective radiologic evidence was not considered disease progression in the primary efficacy analysis.
次要结局
- Maximum Concentration (Cmax) of alpelisib and olaparib(Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose))
- Time to reach maximum concentration (Tmax) of alpelisib and olaparib(Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose))
- Overall survival(From randomization until death, assessed up to approximately 44 months)
- Area under the curve calculated to the end of a dosing interval (tau) at steady-state (AUCtau) of alpelisib and olaparib(Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose))
- Area under the curve from time zero to the last measurable concentration sampling time (AUClast)of alpelisib and olaparib(Day 8 Cycle 1 (pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dose), Day 1 on Cycle 2, 4 and 8 (pre-dose))
- Number of participants with dose interruptions and dose reductions(From randomization until end of treatment, assessed up to approximately 18 months)
- Dose intensity(From randomization until end of treatment, assessed up to approximately 18 months)
- Time to definitive deterioration of the Eastern Cooperative Oncology Group (ECOG) performance status (PS)(Up to approximately 18 months)
- Overall Response Rate (ORR) with confirmed response based on BIRC assessment according to RECIST 1.1 criteria(Up to approximately 23 months)
- Clinical benefit rate (CBR) with confirmed response based on BIRC assessment according to RECIST 1.1(Up to approximately 23 months)
- Duration of response (DOR) with confirmed response based on BIRC assessment and according to RECIST 1.1(From first documented response to first documented progression or death, assessed up to approximately 23 months)
- Time to response (TTR) based on BIRC assessment and according to RECIST 1.1(From the date of randomization to the first documented response, assessed through Month 12)
- Change from baseline in Function Assessment of Cancer Therapy-Ovarian Trial Outcome Index (FACT-O TOI)(Baseline, then every 8 weeks for 18 months, every 12 weeks thereafter until RECIST 1.1 progression, death, consent withdrawal, loss to follow-up, participant/guardian decision, and at End of Treatment (EOT) within 14 days from last dose.)